Lentiviral overexpression of VEGFC in transplanted MSCs leads to resolution of swelling in a mouse tail lymphedema model.

BACKGROUND: Dysfunction of the lymphatic system following injury, disease, or cancer treatment can lead to lymphedema, a debilitating condition with no cure. Despite the various physical therapy and surgical options available, most treatments are palliative and fail to address the underlying lymphatic vascular insufficiency driving lymphedema progression. Stem cell therapy provides a promising alternative in the treatment of various chronic diseases with a wide range of therapeutic effects that reduce inflammation, fibrosis, and oxidative stress, while promoting lymphatic vessel (LV) regeneration. Specifically, stem cell transplantation is suggested to promote LV restoration, rebuild lymphatic circulation, and thus potentially be utilized towards an effective lymphedema treatment. In addition to stem cells, studies have proposed the administration of vascular endothelial growth factor C (VEGFC) to promote lymphangiogenesis and decrease swelling in lymphedema. AIMS: Here, we seek to combine the benefits of stem cell therapy, which provides a cellular therapeutic approach that can respond to the tissue environment, and VEGFC administration to restore lymphatic drainage. MATERIALS & METHODS: Specifically, we engineered mesenchymal stem cells (MSCs) to overexpress VEGFC using a lentiviral vector (hVEGFC MSC) and investigated their therapeutic efficacy in improving LV function and tissue swelling using near infrared (NIR) imaging, and lymphatic regeneration in a single LV ligation mouse tail lymphedema model. RESULTS: First, we showed that overexpression of VEGFC using lentiviral transduction led to an increase in VEGFC protein synthesis in vitro. Then, we demonstrated hVEGFC MSC administration post-injury significantly increased the lymphatic contraction frequency 14-, 21-, and 28-days post-surgery compared to the control animals (MSC administration) in vivo, while also reducing tail swelling 28-days post-surgery compared to controls. CONCLUSION: Our results suggest a therapeutic potential of hVEGFC MSC in alleviating the lymphatic dysfunction observed during lymphedema progression after secondary injury and could provide a promising approach to enhancing autologous cell therapy for treating lymphedema.

Longitudinal Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Pharmacotherapy in Major Depressive Disorder in Older Adults: Phase 2 of the PRIDE Study.

OBJECTIVE: There is limited information regarding neurocognitive outcomes of right unilateral ultrabrief pulse width electroconvulsive therapy (RUL-UB ECT) combined with pharmacotherapy in older adults with major depressive disorder. We report longitudinal neurocognitive outcomes from Phase 2 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHOD: After achieving remission with RUL-UB ECT and venlafaxine, older adults (≥60 years old) were randomized to receive symptom-titrated, algorithm-based longitudinal ECT (STABLE) plus pharmacotherapy (venlafaxine and lithium) or pharmacotherapy-only. A comprehensive neuropsychological battery was administered at baseline and throughout the 6-month treatment period. Statistical significance was defined as a p-value of less than 0.05 (two-sided test). RESULTS: With the exception of processing speed, there was statistically significant improvement across most neurocognitive measures from baseline to 6-month follow-up. There were no significant differences between the two treatment groups at 6 months on measures of psychomotor processing speed, autobiographical memory consistency, short-term and long-term verbal memory, phonemic fluency, inhibition, and complex visual scanning and cognitive flexibility. CONCLUSION: To our knowledge, this is the first report of neurocognitive outcomes over a 6-month period of an acute course of RUL-UB ECT followed by one of 2 strategies to prolong remission in older adults with major depression. Neurocognitive outcome did not differ between STABLE plus pharmacotherapy versus pharmacotherapy alone over the 6-month continuation treatment phase. These findings support the safety of RUL-UB ECT in combination with pharmacotherapy in the prolonging of remission in late-life depression.

Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Venlafaxine in Geriatric Depression: Phase 1 of the PRIDE Study.

OBJECTIVE: There is limited information regarding the tolerability of electroconvulsive therapy (ECT) combined with pharmacotherapy in elderly adults with major depressive disorder (MDD). Addressing this gap, we report acute neurocognitive outcomes from Phase 1 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHODS: Elderly adults (age ≥60) with MDD received an acute course of 6 times seizure threshold right unilateral ultrabrief pulse (RUL-UB) ECT. Venlafaxine was initiated during the first treatment week and continued throughout the study. A comprehensive neurocognitive battery was administered at baseline and 72 hours following the last ECT session. Statistical significance was defined as a two-sided p-value of less than 0.05. RESULTS: A total of 240 elderly adults were enrolled. Neurocognitive performance acutely declined post ECT on measures of psychomotor and verbal processing speed, autobiographical memory consistency, short-term verbal recall and recognition of learned words, phonemic fluency, and complex visual scanning/cognitive flexibility. The magnitude of change from baseline to end for most neurocognitive measures was modest. CONCLUSION: This is the first study to characterize the neurocognitive effects of combined RUL-UB ECT and venlafaxine in elderly adults with MDD and provides new evidence for the tolerability of RUL-UB ECT in an elderly sample. Of the cognitive domains assessed, only phonemic fluency, complex visual scanning, and cognitive flexibility qualitatively declined from low average to mildly impaired. While some acute changes in neurocognitive performance were statistically significant, the majority of the indices as based on the effect sizes remained relatively stable.

Safe resumption of maintenance electroconvulsive therapy 12 days after surgical repair of hip fracture.

Hip fractures are a common injury affecting older individuals, especially women with osteoporosis. When patients who are at risk for hip fractures or who have had such a fracture that was recently repaired require electroconvulsive therapy, care must be taken to ensure complete muscle relaxation. Adequate muscle relaxation can be achieved using a dose of succinylcholine of approximately 1 mg/kg in most patients, but for patients who are at risk for complications resulting from inadequate muscle relaxation, the dose of succinylcholine may need to be increased by 40% to 50% to ensure complete relaxation.

Depression severity in electroconvulsive therapy (ECT) versus pharmacotherapy trials.

OBJECTIVE: We sought to compare the level of severity of depressive symptoms on entry into electroconvulsive therapy (ECT) clinical trials versus pharmacotherapy clinical trials. DATA SOURCES: English-language MEDLINE/PubMed publication databases were searched for ECT literature (search terms: ECT, electroconvulsive therapy, depression, and Hamilton) for clinical trials in which depressed patients had baseline Hamilton Rating Scale for Depression (HRSD) scores. For comparison, we used a convenience sample of 7 large pharmacotherapy trials in major depression (N = 3677). The search included articles from 1960 to 2011. STUDY SELECTION: We included 100 studies that met the following criteria: ECT trial for depression, patients adequately characterized by diagnosis at baseline, and patients rated at baseline by 15-item HRSD (HRSD15), HRSD17, HRSD21, HRSD24, or HRSD28, with mean (SD) and sample size (n) reported. For the comparator pharmacotherapy trials, we chose to use a subset of the studies (excluding one study of minor depression) in the widely publicized meta-analysis of Fournier et al, as well as the STAR*D study and one additional study by Shelton et al. This provided 7 studies of major depression using HRSD17 (total N = 3677). DATA EXTRACTION: Data extracted included number of subjects and baseline and final HRSD scores, with mean (SD) values. RESULTS: Of 100 ECT studies, 56 studies (N = 2243) used the HRSD17 version. The mean baseline HRSD17 score in the ECT trials was 27.6, the mean in the pharmacotherapy trials was 21.94, a statistically, and clinically, significant difference. In a subanalysis of the 16 ECT studies that used the HRSD24 version, the mean baseline score was 32.2. CONCLUSIONS: This selective literature review confirms that patients who entered ECT clinical trials were more severely ill than those who entered the selected comparator pharmacotherapy trials. Such data highlight the critical role of ECT in the treatment of severe and treatment-resistant mood disorders.

Electroconvulsive therapy (ECT) in Parkinson's disease: ECS and dopamine enhancement.

INTRODUCTION: In addition to its effects in major psychiatric illness, electroconvulsive therapy (ECT) is known to have a beneficial effect on the core motor symptoms of Parkinson's disease (PD). This effect is believed to be mediated via dopamine in the striatum. Electroconvulsive shock (ECS), the animal analogue of ECT, is the model in which investigators have sought to elucidate the specific dopaminergic mechanisms by which ECT exerts its therapeutic effect in PD. Electroconvulsive shock has been given to intact animals as well as to animals with neurotoxic lesions that create parkinsonism. METHODS: In this paper, we selectively review the electroconvulsive shock literature on dopamine in the striatum. RESULTS: Electroconvulsive shock, and by extension, ECT, is associated with increased dopamine release and modulation of dopamine receptors. CONCLUSION: Better understanding of how ECT works to enhance dopaminergic systems in the brain could help to make it a more accepted treatment for PD.

Dosing and effectiveness of ketamine anesthesia for electroconvulsive therapy (ECT): a case series.

OBJECTIVE: To provide additional data about the clinical efficacy and dosing range for ketamine used as the induction agent in electroconvulsive therapy (ECT). METHOD: We reviewed the clinical data in our academic hospital ECT service over the last four years for patients who had received ketamine as the sole, or adjunctive, anesthesia induction agent. We extracted clinical data about antidepressant response as well as absolute and weight-based dosing for ketamine. RESULTS: We found nine patients who were treated with ketamine as the anesthetic at some point during the course of their treatment (eight as the sole agent, one as adjunctive). The median induction dose for ketamine was 1.1 mg/kg. For most patients, there was demonstrable clinical benefit. CONCLUSIONS: Ketamine has a role as an alternative induction anesthetic agent in ECT. Our case series adds to the literature on the concomitant use of ECT and ketamine.

Lymphatic endothelial cell-targeting lipid nanoparticles delivering VEGFC mRNA improve lymphatic function after injury.

Dysfunction of the lymphatic system following injury, disease, or cancer treatment can lead to lymphedema, a debilitating condition with no cure. Advances in targeted therapy have shown promise for treating diseases where conventional therapies have been ineffective and lymphatic vessels have recently emerged as a new therapeutic target. Lipid nanoparticles (LNPs) have emerged as a promising strategy for tissue specific delivery of nucleic acids. Currently, there are no approaches to target LNPs to lymphatic endothelial cells, although it is well established that intradermal (ID) injection of nanoparticles will drain to lymphatics with remarkable efficiency. To design an LNP that would effectively deliver mRNA to LEC after ID delivery, we screened a library of 150 LNPs loaded with a reporter mRNA, for both self-assembly and delivery in vivo to lymphatic endothelial cells (LECs). We identified and validated several LNP formulations optimized for high LEC uptake when administered ID and compared their efficacy for delivery of functional mRNA with that of free mRNA and mRNA delivered with a commercially available MC3-based LNP (Onpattro™). The lead LEC-specific LNP was then loaded with VEGFC mRNA to test the therapeutic advantage of the LEC-specific LNP (namely, LNP7) for treating a mouse tail lymphatic injury model. A single dose of VEGFC mRNA delivered via LNP7 resulted in enhanced LEC proliferation at the site of injury, and an increase in lymphatic function up to 14-days post-surgery. Our results suggest a therapeutic potential of VEGFC mRNA lymphatic-specific targeted delivery in alleviating lymphatic dysfunction observed during lymphatic injury and could provide a promising approach for targeted, transient lymphangiogenic therapy.

Electroconvulsive therapy (ECT) for catatonia in a patient with schizophrenia and synthetic cannabinoid abuse: a case report.

We present the case of a young man with a long-standing history of schizophrenia who presented with severe and life-threatening catatonia in the setting of synthetic cannabis use who was successfully treated with electroconvulsive therapy. To our knowledge, this is the first reported case of severe and persistent catatonia in the setting of synthetic cannabis use and the first documented successful treatment.

Exploring predoctoral dental student use of YouTube as a learning tool for clinical endodontic procedures.

PURPOSE/OBJECTIVES: The goal of the present study was to examine perceived barriers to achieving clinical competence in endodontics and explain how YouTube is used to supplement formal education in this discipline. METHODS: Postgraduate endodontic students conducted focus groups with fourth-year dental students at NYU College of Dentistry. The discussion was facilitated by a semistructured interview guide. Open-ended questions about participants' perceived barriers to clinical competency in endodontics, experiences using YouTube to learn about clinical endodontics, and preferences for video format learning were asked. Demographic information was gathered. Thematic analysis of data was conducted and data collection was terminated once saturation was achieved. RESULTS: Thirty fourth-year dental students were enrolled in the study. The majority, 96.7%, reported using YouTube as a learning tool for dental procedures and 83.3% to learn about endodontics, specifically. The following domains were explored during data analysis: barriers to clinical competency, YouTube uses/experiences, and content preferences. The following themes within barriers to clinical competency were identified: psychological, educational, and clinical. Within the YouTube domain, the following themes were examined: goals of use, timing and frequency of use, search strategies, benefit/ shortcomings of YouTube, and validity of content. Students primarily used YouTube to enhance confidence and understand procedural flow. CONCLUSION: YouTube videos were primarily used to help students overcome perceived educational and psychological barriers that resulted in gaps in confidence and knowledge of performing endodontic procedures. Dental students placed high value on easily accessible video content of limited duration, where clinical procedures were performed on live patients.

CPT1A Supports Castration-Resistant Prostate Cancer in Androgen-Deprived Conditions.

Prostate cancer (PCa) is the most common cancer in men, and the global burden of the disease is rising. The majority of PCa deaths are due to metastasis that are highly resistant to current hormonal treatments; this state is called castration-resistant prostate cancer (CRPC). In this study, we focused on the role of the lipid catabolism enzyme CPT1A in supporting CRPC growth in an androgen-dependent manner. We found that androgen withdrawal promoted the growth of CPT1A over-expressing (OE) tumors while it decreased the growth of CPT1A under-expressing (KD) tumors, increasing their sensitivity to enzalutamide. Mechanistically, we found that CPT1A-OE cells burned more lipid and showed increased histone acetylation changes that were partially reversed with a p300 specific inhibitor. Conversely, CPT1A-KD cells showed less histone acetylation when grown in androgen-deprived conditions. Our results suggest that CPT1A supports CRPC by supplying acetyl groups for histone acetylation, promoting growth and antiandrogen resistance.

Design of Large-Scale Reporter Construct Arrays for Dynamic, Live Cell Systems Biology.

Dynamic systems biology aims to identify the molecular mechanisms governing cell fate decisions through the analysis of living cells. Large scale molecular information from living cells can be obtained from reporter constructs that provide activities for either individual transcription factors or multiple factors binding to the full promoter following CRISPR/Cas9 directed insertion of luciferase. In this report, we investigated the design criteria to obtain reporters that are specific and responsive to transcription factor (TF) binding and the integration of TF binding activity with genetic reporter activity. The design of TF reporters was investigated for the impact of consensus binding site spacing sequence and off-target binding on the reporter sensitivity using a library of 25 SMAD3 activity reporters with spacers of random composition and length. A spacer was necessary to quantify activity changes after TGFß stimulation. TF binding site prediction algorithms (BEEML, FIMO and DeepBind) were used to predict off-target binding, and nonresponsiveness to a SMAD3 reporter was correlated with a predicted competitive binding of constitutively active p53. The network of activity of the SMAD3 reporter was inferred from measurements of TF reporter library, and connected with large-scale genetic reporter activity measurements. The integration of TF and genetic reporters identified the major hubs directing responses to TGFß, and this method provided a systems-level algorithm to investigate cell signaling.

Right Unilateral Ultrabrief Pulse ECT in Geriatric Depression: Phase 1 of the PRIDE Study.

OBJECTIVE: The Prolonging Remission in Depressed Elderly (PRIDE) study evaluated the efficacy of right unilateral ultrabrief pulse electroconvulsive therapy (ECT) combined with venlafaxine for the treatment of geriatric depression. METHOD: PRIDE was a two-phase multisite study. Phase 1 was an acute course of right unilateral ultrabrief pulse ECT, combined with open-label venlafaxine at seven academic medical centers. In phase 2 (reported separately), patients who had remitted were randomly assigned to receive pharmacotherapy (venlafaxine plus lithium) or pharmacotherapy plus continuation ECT. In phase 1, depressed patients received high-dose ECT (at six times the seizure threshold) three times per week. Venlafaxine was started during the first week of treatment and continued throughout the study. The primary outcome measure was remission, assessed with the 24-item Hamilton Depression Rating Scale (HAM-D), which was administered three times per week. Secondary outcome measures were post-ECT reorientation and safety. Paired t tests were used to estimate and evaluate the significance of change from baseline in HAM-D scores. RESULTS: Of 240 patients who entered phase 1 of the study, 172 completed it. Overall, 61.7% (148/240) of all patients met remission criteria, 10.0% (24/240) did not remit, and 28.3% (68/240) dropped out; 70% (169/240) met response criteria. Among those who remitted, the mean decrease in HAM-D score was 24.7 points (95% CI=23.4, 25.9), with a mean final score of 6.2 (SD=2.5) and an average change from baseline of 79%. The mean number of ECT treatments to remission was 7.3 (SD=3.1). CONCLUSIONS: Right unilateral ultrabrief pulse ECT, combined with venlafaxine, is a rapidly acting and highly effective treatment option for depressed geriatric patients, with excellent safety and tolerability. These data add to the evidence base supporting the efficacy of ECT to treat severe depression in elderly patients.

A Novel Strategy for Continuation ECT in Geriatric Depression: Phase 2 of the PRIDE Study.

OBJECTIVE: The randomized phase (phase 2) of the Prolonging Remission in Depressed Elderly (PRIDE) study evaluated the efficacy and tolerability of continuation ECT plus medication compared with medication alone in depressed geriatric patients after a successful course of ECT (phase 1). METHOD: PRIDE was a two-phase multisite study. Phase 1 was an acute course of right unilateral ultrabrief pulse ECT, augmented with venlafaxine. Phase 2 compared two randomized treatment arms: a medication only arm (venlafaxine plus lithium, over 24 weeks) and an ECT plus medication arm (four continuation ECT treatments over 1 month, plus additional ECT as needed, using the Symptom-Titrated, Algorithm-Based Longitudinal ECT [STABLE] algorithm, while continuing venlafaxine plus lithium). The intent-to-treat sample comprised 120 remitters from phase 1. The primary efficacy outcome measure was score on the 24-item Hamilton Depression Rating Scale (HAM-D), and the secondary efficacy outcome was score on the Clinical Global Impressions severity scale (CGI-S). Tolerability as measured by neurocognitive performance (reported elsewhere) was assessed using an extensive test battery; global cognitive functioning as assessed by the Mini-Mental State Examination (MMSE) is reported here. Longitudinal mixed-effects repeated-measures modeling was used to compare ECT plus medication and medication alone for efficacy and global cognitive function outcomes. RESULTS: At 24 weeks, the ECT plus medication group had statistically significantly lower HAM-D scores than the medication only group. The difference in adjusted mean HAM-D scores at study end was 4.2 (95% CI=1.6, 6.9). Significantly more patients in the ECT plus medication group were rated "not ill at all" on the CGI-S compared with the medication only group. There was no statistically significant difference between groups in MMSE score. CONCLUSIONS: Additional ECT after remission (here operationalized as four continuation ECT treatments followed by further ECT only as needed) was beneficial in sustaining mood improvement for most patients.

Case report: transient left bundle branch block associated with ECT.

We present the first reported case of transient left bundle branch block (LBBB) occurring during electroconvulsive therapy (ECT). LBBB is an important clinical finding, as it is associated with a significant increase in mortality. Physicians providing ECT should be aware of the significance of new-onset LBBB; it may occur during treatment.